Nora T. Kizer

The role of neoadjuvant chemotherapy in the management of patients with advanced stage ovarian cancer: survey results from members of the Society of Gynecologic Oncologists.

OBJECTIVE Recent randomized controlled data suggest that neoadjuvant chemotherapy (NACT) with interval debulking (ID) may produce similar overall survival and progression free survival compared to standard primary cytoreduction followed by chemotherapy. The object of our study was to assess current patterns of care among members of the Society of Gynecologic Oncologists (SGO), specifically collating their opinions on and use of NACT for advanced stage ovarian cancer. METHODS A 20-item questionnaire was sent to all working e-mail addresses of SGO members (n=1137). The data was collected and analyzed using descriptive statistics with commercially available online survey software. The Chi-square test for independence was used to determine differences in responses between groups. RESULTS Of 339 (30%) responding members, most rarely employ NACT, with 60% of respondents using NACT in less than 10% of advanced stage ovarian cancer cases. Respondents did not consider available evidence sufficient to justify NACT followed by ID (82%), nor did most think it should be preferred (74%). Sixty-two percent of respondents thought it was impossible to accurately predict preoperatively whether an optimal cytoreduction is possible. Thirty-nine percent believed that women with bulky upper abdominal disease on preoperative imaging would benefit from NACT versus primary debulking. If gross disease were found at ID, 43% would continue to treat with IV chemotherapy, and 42% would place an IP port if optimally cytoreduced. When ID reveals microscopic disease, 51% would continue IV treatment and the remaining IP therapy. Eighty-six percent of the respondents believed that both biological and surgical factors determine patient outcomes. CONCLUSIONS The majority of responding SGO members do not treat patients with NACT followed by ID. Currently available studies of NACT/ID have been insufficient to convince most gynecologic oncologists to incorporate it into practice. Our results provide a benchmark against which further research can assess the penetration of NACT/ID into clinical practice.

The effects of body mass index on complications and survival outcomes in patients with cervical carcinoma undergoing curative chemoradiation therapy

The effect of body mass index (BMI) on treatment outcomes for patients with locally advanced cervical carcinoma who receive definitive chemoradiation is unclear.

Report of two cases of rasburicase-induced methemoglobinemia

Rasburicase, a recombinant form of urate oxidase, in 2002 received FDA approval in the prevention of hyperuricemia precipitating acute renal failure in tumor lysis syndrome among the pediatric population. Correction of the hyperuricemia is important as the acute renal failure in tumor lysis syndrome is thought to be due to an acute uric acid nephropathy secondary to uric acid precipitation in the renal tubules. Urate oxidase catalyses the oxidation of uric acid to allantoin, which is shown to be 5 – 10-times more soluble in urine than uric acid [1]. Previously, Uricozyme, a non-recombinant urate oxidase purified from Aspergillus flavus, was available and used in Europe for over two decades. However, it was associated with high rates (4.5%) of acute hypersensitivity reactions. With the development of rasburicase from a genetically modified strain of Saccharomyces cerevisiae using cDNA coding cloned from Aspergillus flavus, the side effect profile was thought to be much improved. Two large multicenter trials have since been published examining the safety and efficacy of the drug and have shown a decrease in adverse events while still maintaining equivalent efficacy [2,3]. Such a development is extremely valuable as tumor lysis syndrome is considered a life threatening metabolic complication associated with high rates of acute renal failure, seizures and cardiac arrhythmias. Despite the more favorable side effect profile of rasburicase, the FDA did issue a boxed warning regarding the potential for methemoglobinemia. Rasburicase can cause hemolytic anemia and methemoglobinemia secondary to oxidative stress created by the metabolic byproduct, hydrogen peroxide, produced during the breakdown of urate to allantoin. The three clinical trials performed prior to FDA approval reported only two cases of methemoglobinemia out of 265 patients (51%). It was not noted if either patient had glucose-6-phosphate dehydrogenase deficiency or a cytochrome b5 reductase deficiency. Both did experience severe hypoxemia that responded to appropriate medical support measures. After FDA approval of rasburicase, there has been only one published case report of methemoglobinemia with hemolysis in a G6PD deficient patient [4]. Patients with G6PD deficiency are at an increased risk secondary to their inability to reduce nicotinamide adenine dincucleotide phosphate (NADP) to NADPH which is an essential cofactor in the detoxification of oxygen radicals. It has been recommended to screen patients for this deficiency prior to implementing rasburicase therapy in cancer patients. Additionally, there has been one prior case report describing methemoglobinemia induced by routine Uricozyme administration in a non-G6PD deficient patient [5]. However, there have been no reports of rasburicase-induced methemoglobinemia in non-G6PD deficient patients. Here we report two cases of methemoglobinemia in response to rasburicase in two patients without a history of G6PD deficiency.

Polymorphisms in MMP9 and SIPA1 are associated with increased risk of nodal metastases in early stage cervical cancer

OBJECTIVE Heritable polymorphisms modulate metastatic efficiency in Cancer Single nucleotide polymorphisms (SNPs) in MMP9 (rs17576) and SIPA1 (rs746429, rs931127) have been associated with nodal metastases in multiple cancers. We investigated the association of these SNPs with nodal metastases in early-stage cervical cancer. METHODS Consecutive patients with stage IB cervical cancer who underwent a pelvic lymph node (LN) dissection were included. Cases (>1 positive LN, n=101) were compared with controls (negative LN pathology, n=273). Genotyping was performed on genomic DNA in the 3 SNPs using a TaqMan assay and correlated with clinical variables. RESULTS The G allele at SIPA1 rs931127 was associated with an increased risk of nodal disease (OR 1.9, P=0.03) and approached significance at SIPA 1 rs746429 (OR 2.2, P=0.09) and MMP9 rs17576 (OR 1.5, 0.08). In patients with stage Ib1 lesions (n=304), the G allele at both SIPA1 SNPs was associated with LN metastases (rs746429 OR 10.1, P=0.01; rs931127 OR 2.4, P=0.01). In patients with no lymph vascular space invasion, SIPA1 SNPs were again associated with LN metastases, and all patients with nodal disease had at least one G allele at SIPA1 rs746429. CONCLUSIONS In this case-control study, SNPs in SIPA1 varied statistically in cervical cancer patients with and without nodal metastases and in MMP9 after controlling for stage and lymphvascular space invasion. Further work is needed to characterize inherited polymorphisms that provide a permissive background for the metastatic cascade.

Surgery in the pregnant patient.

The key pregnancy-related physiological maternal and fetal changes that occur and the modifications to standard surgical approaches that can impact surgical outcomes are important to recognize. Surgery during pregnancy can be safe and effective. Laparoscopy has become an acceptable alternative to the standard laparotomy and should be considered when surgeons with appropriate skills and experience are available. Care of these patients should always involve a multidisciplinary team with the goal to optimize outcomes for both the mother and the fetus.

The role of PET/CT in the management of patients with cervical cancer: practice patterns of the members of the Society of Gynecologic Oncologists.

OBJECTIVES Recent data has highlighted the role of PET/CT in the pretreatment evaluation and follow-up of patients with cervical cancer. The objective of our study was to assess the acceptance of PET/CT into the management of patients with cervical cancer. We also explored potential barriers to the use of these imaging modalities in patients with cervical cancer. METHODS A 14-item electronic questionnaire was initially sent to all working addresses of members of the SGO (n=1048). An opt-out option was offered. For members who did not respond within 3 weeks, a second electronic invitation was sent. A third request was finally sent to further improve response rates. Data were collected and analyzed using a commercially available on-line survey database. RESULTS A total of 305 responses were collected for an overall 30% response rate. PET/CT appears to be widely available (99%) and accessible (75%) in most practices. Although 83% of members order routine CT imaging for all newly diagnosed cervical cancer cases, only 28% routinely order a PET/CT. Conversely, 64% would order a PET/CT for newly diagnosed patients with advanced disease or those at high risk for distant metastatic disease. Most members (82%) do not routinely use PET/CT to assess response to treatment. Twenty percent of members believe that no useful prognostic information can be obtained from routine use of molecular imaging in patients with cervical cancer. The most common barriers for use of PET/CT cited by members were perceived lack of third-party payer coverage and lack of scientific evidence. CONCLUSIONS Despite clear scientific data supporting the use of PET/CT in patients with cervical cancer and apparent widespread availability, this imaging modality remains highly underutilized in clinical practice. Clarifying insurance coverage early in the evaluation process and replicating studies that have shown effectiveness of PET/CT in multiple roles may improve adoption of this potentially useful imaging modality.

Glycogen synthase kinase 3β inhibition as a therapeutic approach in the treatment of endometrial cancer

Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3β (GSK3β), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3β inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3β by either lithium chloride (LiCl) or specific GSK3β inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3β activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth.

A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients

OBJECTIVES Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications. METHODS Women with a body mass index (BMI) ≥30 kg/m(2) undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Campers fascia, closure of Campers fascia with 3-0 plain catgut suture and skin closure with staples. Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway. RESULTS 105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30-39.9 kg/m(2) had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m(2) (23% vs 59%, p<0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI <40 kg/m(2) (OR 0.40, 95% C.I.: 0.18-0.89). CONCLUSION This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30-39.9 kg/m(2).

Cardiac arrest during laparotomy with argon beam coagulation of metastatic ovarian cancer.

Background: The argon beam coagulation (ABC) is a safe and effective tool for surgical cytoreduction of metastatic ovarian carcinomas. Case: A 66-year-old woman with newly diagnosed advanced stage epithelial ovarian cancer underwent primary cytoreductive surgery involving ABC of tumor implants. Intraoperatively, she experienced cardiac arrest during use of the ABC. She was successfully resuscitated. The etiology of the arrest was thought to be secondary to a venous gas embolism. Conclusions: The risk associated with venous gas embolism in a laparotomy case is exceedingly low. This is the first case report of venous gas embolism during ABC in a surgical procedure for gynecologic malignancy. Proper monitoring and support services should always be immediately available when using ABC.

Clinicopathologic characteristics and survival of patients with gynecologic malignancies metastatic to the brain

OBJECTIVE No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment. METHODS This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Students paired t-test (for marker expression) and Kaplan-Meier test (for correlations). RESULTS On univariate analysis, primary ovarian disease, CA-125<81units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19-5.93; p=0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls (p<0.0001). None of the molecular markers were significantly associated with survival. CONCLUSIONS Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases.